Nuclear Receptor Corepressor Research Articles

SAT-559 Intranuclear Dynamics of RTHα Mutant Thyroid Hormone Receptors

: Resistance to Thyroid Hormone α (RTHα), a reduced sensitivity to thyroid hormone (T3) in peripheral tissues, is caused by mutations in thyroid hormone receptor α (TRα), a nuclear receptor that regulates gene expression when bound to T3. These mutations often result in receptors incapable of binding T3. All mutations characterized in RTHα, thus far, have been found in the ligand binding domain (LBD), some of which result in truncated proteins lacking all or part of helix 12. Some studies have shown that Nuclear Receptor Corepressor 1 (NCoR1), which interacts with the hinge region of TRα (the region between the DNA-binding domain and LBD) has a higher affinity for RTHα mutants compared to wild-type TRα, supporting the hypothesis that helix 12 of the LBD also functions to disassociate NCoR1 from TRα when it is bound to T3 (1, 2). We proposed that this increased affinity for NCoR1 alters the mobility of the TRα in the nucleus, impacting its function. As a first step in in testing this model, we used Fluorescence Recovery after Photobleaching (FRAP) to examine the effects of select RTHα mutations, Ala382ProfsX7 and F397fs406X, on nuclear localization and intranuclear mobility. After transfecting HeLa cells with expression plasmids for green fluorescent protein (GFP)-tagged wild-type TRα and each of the mutants, we first assessed their intracellular distribution and initial intranuclear mobility. Although wild-type TRα is known to shuttle between the nucleus and cytoplasm, it is primarily localized to the nucleus at a steady state. Here we show that TR-Ala382ProfsX7 and F397fs406X are also primarily localized to the nucleus. FRAP revealed that wild-type TRα is highly dynamic within the nucleus, with recovery half-times ranging from 0.74 to 0.95 seconds and 97.4% (n=3, 20 cells per replicate) of TRα in the mobile fraction, indicating that the receptor rapidly dissociates and reassociates with DNA binding sites and/ or other nuclear binding sites. There was no significant difference in intranuclear dynamics between wild-type TRα and the RTHα mutants, TR-Ala382ProfsX7 and F397fs406X. Next, we wanted to determine the effects of T3 on intranuclear mobility and found that recovery half-times and the percentage of receptors in the mobile fraction were T3 independent for both wild-type TRα and RTHα mutants. Investigation of the effects of overexpression or knock down of NCoR1 will provide further insight into the impact of altered binding affinity for NCoR1 on the intranuclear dynamics of RTHα mutants.

Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPAR\u03b1

Obesity triggers the development of non-alcoholic fatty liver disease (NAFLD), which involves alterations of regulatory transcription networks and epigenomes in hepatocytes. Here we demonstrate that G protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor (NCOR) and histone deacetylase 3 (HDAC3) complex, has a central role in these alterations and accelerates the progression of NAFLD towards non-alcoholic steatohepatitis (NASH). Hepatocyte-specific Gps2 knockout in mice alleviates the development of diet-induced steatosis and fibrosis and causes activation of lipid catabolic genes. Integrative cistrome, epigenome and transcriptome analysis identifies the lipid-sensing peroxisome proliferator-activated receptor α (PPARα, NR1C1) as a direct GPS2 target. Liver gene expression data from human patients reveal that Gps2 expression positively correlates with a NASH/fibrosis gene signature. Collectively, our data suggest that the GPS2-PPARα partnership in hepatocytes coordinates the progression of NAFLD in mice and in humans and thus might be of therapeutic interest.

Autophagy regulates lipid metabolism through selective turnover of NCoR1

Selective autophagy ensures the removal of specific soluble proteins, protein aggregates, damaged mitochondria, and invasive bacteria from cells. Defective autophagy has been directly linked to metabolic disorders. However how selective autophagy regulates metabolism remains largely uncharacterized. Here we show that a deficiency in selective autophagy is associated with suppression of lipid oxidation. Hepatic loss of Atg7 or Atg5 significantly impairs the production of ketone bodies upon fasting, due to decreased expression of enzymes involved in β-oxidation following suppression of transactivation by PPARα. Mechanistically, nuclear receptor co-repressor 1 (NCoR1), which interacts with PPARα to suppress its transactivation, binds to the autophagosomal GABARAP family proteins and is degraded by autophagy. Consequently, loss of autophagy causes accumulation of NCoR1, suppressing PPARα activity and resulting in impaired lipid oxidation. These results suggest that autophagy contributes to PPARα activation upon fasting by promoting degradation of NCoR1 and thus regulates β-oxidation and ketone bodies production.

The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPAR\u03b1

The class 3 phosphoinositide 3-kinase (PI3K) is required for lysosomal degradation by autophagy and vesicular trafficking, assuring nutrient availability. Mitochondrial lipid catabolism is another energy source. Autophagy and mitochondrial metabolism are transcriptionally controlled by nutrient sensing nuclear receptors. However, the class 3 PI3K contribution to this regulation is unknown. We show that liver-specific inactivation of Vps15, the essential regulatory subunit of the class 3 PI3K, elicits mitochondrial depletion and failure to oxidize fatty acids. Mechanistically, transcriptional activity of Peroxisome Proliferator Activated Receptor alpha (PPARα), a nuclear receptor orchestrating lipid catabolism, is blunted in Vps15-deficient livers. We find PPARα repressors Histone Deacetylase 3 (Hdac3) and Nuclear receptor co-repressor 1 (NCoR1) accumulated in Vps15-deficient livers due to defective autophagy. Activation of PPARα or inhibition of Hdac3 restored mitochondrial biogenesis and lipid oxidation in Vps15-deficient hepatocytes. These findings reveal roles for the class 3 PI3K and autophagy in transcriptional coordination of mitochondrial metabolism.

Nuclear Receptor Corepressor 1 Regulates Thyroid Hormone Receptor Nuclear Retention

The thyroid hormone receptor (TR) mediates gene transcription in response to thyroid hormone (T3) and significantly affects cell growth, development and metabolism. Although TR shuttles rapidly between the nucleus and cytoplasm, it is primarily nuclear localized at steady state. A shift in the balance between export and import leading to TR mislocalization may correlate with certain cancers or endocrine disorders. Previously, we have identified multiple nuclear localization signals and nuclear export signal within TR that interact with importins and exportins, respectively, to mediate shuttling. Given that TR contains multiple, competing import and export signals, the question arises: what factors are involved in nuclear retention of TR? In addition to DNA‐binding sites, the lab's prior research indicated that nuclear coactivator MED1 facilitates TR nuclear localization. Thus, we hypothesize that certain transcriptional coregulators, including Nuclear Receptor Corepressor 1 (NCoR1), contribute to TR nuclear retention. Using transient transfection assays and fluorescence microscopy, we measured the fluorescent intensity of GFP or mCherry‐tagged TR in the nucleus (N) and cytoplasm (C) of HeLa cells, and then calculated the N/C ratio as an indicator of intracellular localization patterns. We discovered that when NCoR1 is knocked down by shRNA, the amount of TR in the nucleus decreased significantly (lower N/C ratio). Inversely, when NCoR1 is over‐expressed, the amount of TR in the nucleus significantly increased (higher N/C ratio). An even more dramatic cytosolic shift was observed for a TR mutant that cannot bind to NCoR1 (AHT‐TR). Taken together, our results suggest that NCoR1 is a key regulator of TR nuclear retention. This finding will contribute to the development of a dynamic mathematical model that aims to predict TR's N/C ratio during the interaction with different complexes and TR localization's effect on transcriptional output of T3‐dependent genes.Support or Funding InformationNIH 2R15DK058028This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Transducin β-like 1 X-linked receptor 1 (TBLR1) affects RGNNV infection through negative regulation of interferon immune response in orange-spotted grouper, Epinephelus coioides

Transducin β-like 1 X-linked receptor 1 (TBLR1) was identified as an important component of nuclear receptor corepressor (N-CoR) complex, and functionally participated in regulation of transcriptional activation. However, the potential roles of TBLR1 in innate immune response still remain uncertain. In the present work, a novel TBLR1 from orange-spotted grouper, Epinephelus coioides (named as EcTBLR1) was cloned and its effect on fish virus infection was characterized. The full length open reading frame (ORF) of EcTBLR1 was 1548 bp and encoded a putative 515-aa polypeptide, which shared 99% and 95% identity with its homologue from large yellow croaker (Larimichthys crocea) and human (Homo sapiens), respectively. Quantitative PCR (qPCR) analysis revealed a ubiquitous expression of EcTBLR1 in different tissues with remarkable expression in brain, spleen and head-kidney. Subcellular location analysis showed that EcTBLR1 was mainly located in cytoplasm of grouper spleen cells, and partly translocated into nucleus after infection with red spotted grouper nervous necrosis virus (RGNNV). Moreover, RGNNV infection suppressed the protein synthesis of EcTBLR1 in grouper cells. Using RNA interference (RNAi) technology, we found that effective knock-down of EcTBLR1 significantly suppressed the transcription of RGNNV capsid protein (Cp) and RNA-dependent RNA polymerase (RdRp) genes, which implied the crucial role of EcTBLR1 in RGNNV infection. Consistently, overexpression of EcTBLR1 in vitro significantly inhibited IFN promoter activity, as well as the transcription of IFN-related downstream effectors, including interferon stimulated gene 15 (ISG15) and interferon regulatory factor 3 (IRF3). Together, our results for the first time demonstrated that fish TBLR1 might exert critical roles during fish RNA virus replication by negatively regulating interferon response.

Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing

BackgroundRett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (MECP2). Our objective...

The nuclear receptor corepressor NCoR1 regulates hematopoiesis and leukemogenesis in vivo

AbstractEnhanced understanding of normal and malignant hematopoiesis pathways should facilitate the development of effective clinical treatment strategies for hematopoietic malignancies. Nuclear receptor corepressor 1 (NCoR1) has been implicated in transcriptional repression and embryonic organ development, but its role in hematopoiesis is yet to be fully elucidated. Here, we showed that hematopoietic-specific loss of NCoR1 leads to expansion of the hematopoietic stem cell (HSC) pool due to aberrant cell cycle entry of long-term HSCs under steady-state conditions. Moreover, NCoR1-deficient HSCs exhibited normal self-renewal capacity but severely impaired lymphoid-differentiation potential in competitive hematopoietic-reconstitution assays. Transcriptome analysis further revealed that several hematopoiesis-associated genes are regulated by NCoR1. In addition, NCoR1 deficiency in hematopoietic cells delayed the course of leukemia and promoted leukemia cell differentiation in an MLL-AF9–induced mouse model. NCoR1 and its partner, histone deacetylase 3, can modulate histone acetylation and gene transcription through binding the promoter regions of myeloid-differentiation genes. Our collective results support the critical involvement of NCoR1 in normal and malignant hematopoiesis in vivo.

Reciprocal transrepression between FOXF2 and FOXQ1 controls basal‐like breast cancer aggressiveness

FOXF2 and FOXQ1, forkhead box transcription factor superfamily members, are encoded by neighboring genes located on human chromosome 6p25.3 and play opposite roles in epithelial-mesenchymal transition (EMT) and metastasis in basal-like breast cancer (BLBC). However, the relationship between FOXF2 and FOXQ1 in cancer remains unknown. Here, we found mutual transcriptional repression between FOXF2 and FOXQ1, and the reciprocal negative feedback loop controlled EMT, aggressiveness, and chemoresistance in BLBC cells. We further demonstrated that FOXF2 recruited nuclear receptor corepressor 1 and histone deacetylase 3 to the FOXQ1 promoter to inhibit its transcription in BLBC cells, but FOXQ1 did not exert such an effect on FOXF2. Our findings reveal novel mechanisms underlying the determination of BLBC aggressiveness and the transrepressive function of FOXF2 in a basal-like cell subtype-specific manner. Therefore, blocking the vicious cycle of the abnormal reciprocal feedback loop between FOXF2 and FOXQ1 to induce cell differentiation and restore tissue homeostasis is a promising strategy for the treatment of aggressive BLBC.-Kang, L.-J., Yu, Z.-H., Cai, J., He, R., Lu, J.-T., Hou, C., Wang, Q.-S., Li, X.-Q., Zhang, R., Feng, Y.-M. Reciprocal transrepression between FOXF2 and FOXQ1 controls basal-like breast cancer aggressiveness.

Nuclear-cytoplasmic shuttling of class IIa histone deacetylases regulates somatic cell reprogramming.

Class IIa histone deacetylases (HDACs) are a subfamily of HDACs with important functions in development and adult tissue homeostasis. As opposed to other HDACs, they lack catalytic function and bind transcription factors to recruit transcriptional co-regulators, mostly co-repressors such as nuclear receptor co-repressor (NCoR)/silencing mediator of retinoid and thyroid hormone receptor (SMRT). Class IIa HDACs enhance mouse somatic cell reprogramming to induced pluripotent stem cells (iPSCs) by repressing the function of the pro-mesenchymal transcription factor myocyte enhancer factor 2 (MEF2), which is upregulated during this process. Here, we describe, using HDAC4 and 7 as examples, that class IIa HDACs exhibit nuclear-cytoplasmic trafficking in reprogramming, being mostly cytoplasmic in donor fibroblasts and intermediate cells but translocating to the nucleus in iPSCs. Importantly, over-expressing a mutant form of HDAC4 or 7 that becomes trapped in the nucleus enhances the early phase of reprogramming but is deleterious afterwards. The latter effect is mediated through binding to the exogenous reprogramming factors at pluripotency loci, and the subsequent recruitment of NCoR/SMRT co-repressors. Thus, our findings uncover a context-dependent function of class IIa HDACs in reprogramming and further reinforce the idea that recruitment of co-repressors by the exogenous factors is a major obstacle for reactivating the pluripotency network in this process.

Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus-CA3 projection.

Nuclear receptor corepressor 1 (NCOR1) and NCOR2 (also known as SMRT) regulate gene expression by activating histone deacetylase 3 through their Deacetylase Activation Domain (DAD). We show that mice with DAD knock-in mutations have memory deficits, reduced anxiety levels, and reduced social interactions. Mice with NCOR1/2 depletion specifically in GABAergic neurons (NS-V mice) recapitulated the memory deficits and had reduced GABRA2 expression in lateral hypothalamus GABAergic neurons (LHGABA). This was associated with LHGABA neuron hyperexcitability and impaired hippocampal long-term potentiation, through a monosynaptic LHGABA to CA3GABA projection. Optogenetic activation of this projection caused memory deficits, while targeted manipulation of LHGABA or CA3GABA neuron activity reversed memory deficits in NS-V mice. We describe de novo variants in NCOR1, NCOR2 or HDAC3 in patients with intellectual disability or neurodevelopmental defects. These findings identify a hypothalamus–hippocampus projection that may link endocrine signals with synaptic plasticity through NCOR-mediated regulation of GABA signaling.

A Non-canonical Pathway with Potential for Safer Modulation of Transforming Growth Factor-β1 in Steroid-Resistant Airway Diseases

SummaryImpaired therapeutic responses to anti-inflammatory glucocorticoids (GC) in chronic respiratory diseases are partly attributable to interleukins and transforming growth factor β1 (TGF-β1). However, previous efforts to prevent induction of GC insensitivity by targeting established canonical and non-canonical TGF-β1 pathways have been unsuccessful. Here we elucidate a TGF-β1 signaling pathway modulating GC activity that involves LIM domain kinase 2-mediated phosphorylation of cofilin1. Severe, steroid-resistant asthmatic airway epithelium showed increased levels of immunoreactive phospho-cofilin1. Phospho-cofilin1 was implicated in the activation of phospholipase D (PLD) to generate the effector(s) (lyso)phosphatidic acid, which mimics the TGF-β1-induced GC insensitivity. TGF-β1 induction of the nuclear hormone receptor corepressor, SMRT (NCOR2), was dependent on cofilin1 and PLD activities. Depletion of SMRT prevented GC insensitivity. This pathway for GC insensitivity offers several promising drug targets that potentially enable a safer approach to the modulation of TGF-β1 in chronic inflammatory diseases than is afforded by global TGF-β1 inhibition.

Prenatal androgen excess alters the uterine peroxisome proliferator-activated receptor (PPAR) system.

It is known that androgen excess induces changes in fetal programming that affect several physiological pathways. Peroxisome proliferator-activated receptors (PPARs) α, δ and γ are key mediators of female reproductive functions, in particular in uterine tissues. Thus, we aimed to study the effect of prenatal hyperandrogenisation on the uterine PPAR system. Rats were treated with 2mg testosterone from Day 16 to 19 of pregnancy. Female offspring (PH group) were followed until 90 days of life, when they were killed. The PH group exhibited an anovulatory phenotype. We quantified uterine mRNA levels of PPARα (Ppara ), PPARδ (Ppard ), PPARγ (Pparg ), their regulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a ) and nuclear receptor co-repressor 1 (Ncor1 ) and cyclo-oxygenase (COX)-2 (Ptgs2 ), and assessed the lipid peroxidation (LP) index and levels of glutathione (GSH) and prostaglandin (PG) E2 . The PH group showed decreased levels of all uterine PPAR isoforms compared with the control group. In addition, PGE2 and Ptgs2 levels were increased in the PH group, which led to a uterine proinflammatory environment, as was LP, which led to a pro-oxidant status that GSH was not able to compensate for. These results suggest that prenatal exposure to androgen excess has a fetal programming effect that affects the gene expression of PPAR isoforms, and creates a misbalanced oxidant-antioxidant state and a proinflammatory status.

Hairless-knockout piglets generated using the clustered regularly interspaced short palindromic repeat/CRISPR-associated-9 exhibit abnormalities in the skin and thymus.

The nuclear receptor corepressor Hairless (HR) interacts with nuclear receptors and controls expression of specific target genes involved in hair morphogenesis and hair follicle cycling. Patients with HR gene mutations exhibit atrichia, and in rare cases, immunodeficiency. Pigs with HR gene mutations may provide a useful model for developing therapeutic strategies because pigs are highly similar to humans in terms of anatomy, genetics, and physiology. The present study aimed to knockout the HR gene in pigs using the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated-9 (Cas9) system and to investigate the molecular and structural alterations in the skin and thymus. We introduced a biallelic mutation into the HR gene in porcine fetal fibroblasts and generated nine piglets via somatic cell nuclear transfer. These piglets exhibited a lack of hair on the eyelids, abnormalities in the thymus and peripheral blood, and altered expression of several signaling factors regulated by HR. Our results indicate that introduction of the biallelic mutation successfully knocked out the HR gene, resulting in several molecular and structural changes in the skin and thymus. These pigs will provide a useful model for studying human hair disorders associated with HR gene mutations and the underlying molecular mechanisms.

Regulation of histone deacetylase 3 by metal cations and 10-hydroxy-2E-decenoic acid: Possible epigenetic mechanisms of queen-worker bee differentiation.

Histone deacetylases (HDACs) catalyze the hydrolysis of Ɛ-acetyl-lysine residues of histones. Removal of acetyl groups results in condensation of chromatin structure and repression of gene expression. Human class I, II, and IV HDACs are said to be zinc-dependent in that they require divalent zinc ions to catalyze the deacetylase reaction. HDACs are considered potential targets for the treatment of cancer due to their role in regulating transcription. They are also thought to play important roles in the development of organisms such as honey bees. The fatty acid, 10-hydroxy-2E-decenoic acid (10-HDA), which can account for up to 5% of royal jelly composition has been reported as an HDAC inhibitor. The crystal structure of the HDAC3:SMRT complex possesses two monovalent cations (MVCs) labeled as potassium with one MVC binding site near the active site Zn(II) and the second MVC binding site ≥20 Å from the active site Zn(II). We report here the inhibitory effects of excess Zn(II) on the catalytic activity of histone deacetylase 3 (HDAC3) bound to the deacetylase activating domain of nuclear receptor corepressor 2 (NCOR2). We also report the effects of varying concentrations of potassium ions where [K+] up to 10 mM increase HDAC3 activity with a maximum kcat/KM of approximately 80,000 M-1s-1 while [K+] above 10 mM inhibit HDAC3 activity. The inhibition constant (Ki) of 10-HDA was determined to be 5.32 mM. The regulatory effects of zinc, potassium, and 10-HDA concentration on HDAC3 activity suggest a strong correlation between these chemical species and epigenetic control over Apis mellifera caste differentiation among other control mechanisms.

Evaluation of transcriptionally regulated genes identifies NCOR1 in hormone receptor negative breast tumors and lung adenocarcinomas as a potential tumor suppressor gene.

Regulation of transcription is a key process in cellular homeostasis. It depends on regulators that either repress or stimulate the transcription of genes, therefore controlling different biological functions. The Nuclear Receptor Corepressor 1 (NCOR1) is one of those co-repressors that regulate the transcription by facilitating the recruitment of HDAC1, 2, 3, 4, 5 and 7. In our article, by using an in silico approach, we evaluate the mutational status of NCOR1 in breast and lung tumors. We identified that NORC1 is mutated in more than 3% of breast tumors and lung adenocarcinomas and linked this fact with detrimental outcome in some subtypes, particularly in those that are hormone receptor negative. In addition to these findings, as mutations in this gene are deleterious, we confirmed that high levels of this gene were linked with good prognosis in the same tumor subtypes. Findings in the same direction were identified in lung adenocarcinomas, with mutations associated with detrimental prognosis and high expression with better outcome. In conclusion, hereby we describe the presence and prognostic role of mutations in the NCOR1 gene in hormone receptor negative breast and lung adenocarcinomas, and we also confirm that NCOR1 is a tumor suppressor gene. Further studies should be performed to explore therapeutic mechanisms to restore its function.

BAP1 regulation of the key adaptor protein NCoR1 is critical for γ-globin gene repression.

Human globin gene production transcriptionally "switches" from fetal to adult synthesis shortly after birth and is controlled by macromolecular complexes that enhance or suppress transcription by cis elements scattered throughout the locus. The DRED (direct repeat erythroid-definitive) repressor is recruited to the ε-globin and γ-globin promoters by the orphan nuclear receptors TR2 (NR2C1) and TR4 (NR2C2) to engender their silencing in adult erythroid cells. Here we found that nuclear receptor corepressor-1 (NCoR1) is a critical component of DRED that acts as a scaffold to unite the DNA-binding and epigenetic enzyme components (e.g., DNA methyltransferase 1 [DNMT1] and lysine-specific demethylase 1 [LSD1]) that elicit DRED function. We also describe a potent new regulator of γ-globin repression: The deubiquitinase BRCA1-associated protein-1 (BAP1) is a component of the repressor complex whose activity maintains NCoR1 at sites in the β-globin locus, and BAP1 inhibition in erythroid cells massively induces γ-globin synthesis. These data provide new mechanistic insights through the discovery of novel epigenetic enzymes that mediate γ-globin gene repression.

Toxicity of overexpressed MeCP2 is independent of HDAC3 activity.

Duplication of the X-linked MECP2 gene causes a severe neurological syndrome whose molecular basis is poorly understood. To determine the contribution of known functional domains to overexpression toxicity, we engineered a mouse model that expresses wild-type or mutated MeCP2 from the Mapt (Tau) locus in addition to the endogenous protein. Animals that expressed approximately four times the wild-type level of MeCP2 failed to survive to weaning. Strikingly, a single amino acid substitution that prevents MeCP2 from binding to the TBL1X(R1) subunit of nuclear receptor corepressor 1/2 (NCoR1/2) complexes, when expressed at equivalent high levels, was phenotypically indistinguishable from wild type, suggesting that excessive corepressor recruitment underlies toxicity. In contrast, mutations affecting the DNA-binding domain were toxic when overexpressed. As the NCoR1/2 corepressors are thought to act through histone deacetylation by histone deacetylase 3 (HDAC3), we asked whether mutations in NCoR1 and NCoR2 that drastically reduced their ability to activate this enzyme would relieve the MeCP2 overexpression phenotype. Surprisingly, severity was unaffected, indicating that the catalytic activity of HDAC3 is not the mediator of toxicity. Our findings shed light on the molecular mechanisms underlying MECP2 duplication syndrome and call for a re-evaluation of the precise biological role played by corepressor recruitment.

Integrative regulation of physiology by histone deacetylase 3.

Cell-type-specific gene expression is physiologically modulated by the binding of transcription factors to genomic enhancer sequences, to which chromatin modifiers such as histone deacetylases (HDACs) are recruited. Drugs that inhibit HDACs are in clinical use but lack specificity. HDAC3 is a stoichiometric component of nuclear receptor co-repressor complexes whose enzymatic activity depends on this interaction. HDAC3 is required for many aspects of mammalian development and physiology, for example, for controlling metabolism and circadian rhythms. In this Review, we discuss the mechanisms by which HDAC3 regulates cell type-specific enhancers, the structure of HDAC3 and its function as part of nuclear receptor co-repressors, its enzymatic activity and its post-translational modifications. We then discuss the plethora of tissue-specific physiological functions of HDAC3.

Histone deacetylase 2 is essential for LPS‐induced inflammatory responses in macrophages

The role of specific histone deacetylase (HDAC) proteins in regulating the lipopolysaccharide (LPS)‐induced inflammatory response and its underlying mechanisms are unclear. Here, HDAC2, a class I HDAC family protein, is essential for the LPS‐triggered inflammatory response in macrophages. LPS stimulation increases HDAC2 expression in macrophages. Knockdown of HDAC2 decreases the expression of proinflammatory genes, such as IL‐12, TNF‐α and iNOS following stimulation with LPS. The adoptive transfer of HDAC2 knockdown macrophages attenuates the LPS‐triggered innate inflammatory response in vivo, and these mice are less sensitive to endotoxin shock and Escherichia coli‐induced sepsis. Mechanistically, the c‐Jun protein is the main target of HDAC2‐mediated LPS‐induced production of proinflammatory cytokines. Moreover, HDAC2 knockdown increases the expression of c‐Jun, which directly binds the promoters of proinflammatory genes and forms nuclear receptor corepressor complexes to inhibit the transcription of proinflammatory genes in macrophages. These effects are rescued by c‐Jun expression. According to the chromatin immunoprecipitation analysis, HDAC2 also selectively suppresses c‐Jun expression by directly binding to its promoter and modifying histone acetylation after LPS stimulation. Our findings define a new function and mechanism of the HDAC2/c‐Jun signaling network that regulates the LPS‐induced immune response in macrophages.